How Myelofibrosis Stem Cells Manipulate Their Surroundings

A study published in Blood sheds light on one of cancer biology's most pressing questions: How do malignant stem cells not only survive but thrive by manipulating the tissue environment around them?¹ Using a novel laboratory model of myelofibrosis (MF), researchers demonstrated for the first time how diseased blood stem cells and their surrounding support cells engage in complex, multidirectional communication.

What Is Myelofibrosis?

MF is a progressive blood cancer classified as a myeloproliferative neoplasm (MPN). It originates in hematopoietic stem and progenitor cells—cells responsible for producing all blood cell types—and is characterized by a scarring of the bone marrow, enlarged spleen, anemia, and a chronic state of inflammation.²

Over time, the bone marrow's normal architecture is replaced by fibrous tissue, and blood cell production shifts to organs like the spleen that do not normally perform this function. Despite its severity, the precise mechanisms by which MF stem cells dominate and persist have remained poorly understood, largely because existing laboratory models have failed to capture the true complexity of the disease environment.²

A New Model for a Complex Disease

To address this gap, researchers developed a tricultivation system (TCS)—a 3-way cell culture platform that brings together MF patient-derived HSPCs alongside 2 key components of the tumor microenvironment (TME): endothelial cells (ECs), which line blood vessels, and mesenchymal stromal cells (MSCs), which provide structural and signaling support within the bone marrow.¹

Crucially, the ECs and MSCs were sourced from healthy donors, meaning they were not themselves cancerous. This setup allowed the team to isolate and study the consequences of interactions between malignant stem cells and normal microenvironmental cells.¹

The tricultivation system promoted the dominance of the malignant MF clone over normal HSPCs, and the MF stem cells cultured in this way retained their disease-initiating capacity. When transplanted into immunodeficient mice, these cells successfully reproduced hallmark features of MF, including splenomegaly and bone marrow fibrosis. This confirmed that the model preserves the functional identity of MF stem cells in a way that previous methods could not.¹

Inflammation as a Central Driver

Transcriptional profiling revealed that the coculture affected more than just MF HSPCs. The healthy ECs and MSCs were also extensively reprogrammed by their proximity to the malignant cells. Among the many dysregulated pathways identified, a proinflammatory response emerged as the dominant consequence of these interactions. Elevated inflammatory transcripts and increased cytokine production were validated experimentally, suggesting that MF stem cells actively induce inflammation in their surrounding environment.¹

Why It Matters

This research offers the field a simple, reproducible, and biologically faithful platform for studying MF and, more broadly, the interplay between cancer stem cells and their microenvironment. By demonstrating that the TME is not a passive bystander but an active participant in disease progression, the study opens new therapeutic avenues. Targeting the inflammatory crosstalk between MF HSPCs and microenvironmental cells could represent a more effective strategy for disrupting the disease at its root.

REFERENCES

1. Lu M, Mia MB, Xia L, et al. Microenvironmental cell interactions are essential for sustaining functionality of myelofibrosis malignant stem cells. Blood. March 12, 2026. doi.org/10.1182/blood.2025031454

2. Myelofibrosis. Mayo Clinic. May 2, 2025. Accessed April 7, 2026. https://www.mayoclinic.org/diseases-conditions/myelofibrosis/symptoms-causes/syc-20355057